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The new antibiotic specifically binds to the building blocks with unusual intensity and kills the bacteria by destroying their cell wall.
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Clovibactin: Bacterium-Derived New Antibiotic on the Block

Novel antibiotic disrupts peptidoglycan layer's structural integrity, forces autolysin release in Gram-positive bacteria

University of Bonn
Published:Aug 22, 2023
|3 min read
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Researchers from the University of Bonn, the German Center for Infection Research (DZIF), Utrecht University (Netherlands), Northeastern University in Boston (USA), and the company NovoBiotic Pharmaceuticals in Cambridge (USA) have recently discovered and deciphered the mode of action of a new antibiotic. Clovibactin is an antibiotic derived from a soil bacterium. It is highly effective at attacking the bacterial cell wall, including many multiresistant “superbugs.” The results were published in Cell.

“We urgently need new antibiotics to stay ahead in the race against bacteria that have become resistant,” says Tanja Schneider, PhD, professor at the Institute for Pharmaceutical Microbiology, University of Bonn and the University Hospital Bonn. Schneider adds that in recent decades, not many new substances to combat bacterial pathogens have come onto the market. “Clovibactin is novel compared to current antibiotics in use.”

The Institute for Pharmaceutical Microbiology, together with the DZIF, specializes in deciphering the mode of action of antibiotic candidates.

The soil bacterium Eleftheria terrae subspecies carolina carries its place of origin in its name: It was isolated from a soil sample in the state of North Carolina and produces the new antibiotic compound, clovibactin, to protect itself from competing bacteria. “The new antibiotic simultaneously attacks the bacterial cell wall at several sites by blocking essential building blocks,” explains Schneider. It specifically binds to these building blocks with unusual intensity and kills the bacteria by destroying their cell envelope.

Clovibactin surrounds the target like a cage

Research groups from different disciplines and countries worked together to unravel exactly how this works. The team led by Kim Lewis, PhD, professor and director of the Antimicrobial Discovery Center at Northeastern University in Boston and co-founder of NovoBiotic Pharmaceuticals LLC in Cambridge, USA, discovered clovibactin using the iChip technique. The iChip allows bacteria that were previously considered unculturable and unavailable for the development of new antibiotics to be grown in the laboratory.

“Our discovery of this exciting new antibiotic further validates the iCHip culturing technology for finding new therapeutic compounds from previously uncultivated microorganisms,” says Dallas Hughes, PhD, president of NovoBiotic. The company has demonstrated that clovibactin has very good activity against a broad spectrum of bacterial pathogens and has successfully treated mice in preclinical studies.

The mode of action of the new antibiotic was elucidated by researchers led by Schneider. The researchers from Bonn were able to show that clovibactin binds very selectively and with high specificity to pyrophosphate groups of bacterial cell wall components. Markus Weingarth, PhD, assistant professor, and his group from the Department of Chemistry at Utrecht University, Netherlands, uncovered exactly what this interaction looks like. Using solid-state NMR spectroscopy, the researchers deciphered the structure of the complex of clovibactin and the bacterial peptidoglycan precursor lipid II—under conditions similar to those found in the bacterial cell. These studies showed that clovibactin grips around the pyrophosphate group, like a cage.

Combined attack minimizes resistance development

Clovibactin acts primarily on gram-positive bacteria. These include hospital pathogens such as MRSA, as well as tuberculosis pathogens that affect many millions of people worldwide. “We are very confident that the bacteria will not develop resistance to clovibactin so quickly,” says Schneider. This is because the pathogens cannot change the cell wall building blocks so easily to undermine the antibiotic—their Achilles’ heel, therefore, remains.

But clovibactin can do even more. After docking to the target structures, clovibactin forms supramolecular filamentous structures that tightly enclose and further damage the target structures of bacteria. Bacteria that encounter clovibactin are also stimulated to release certain enzymes, known as autolysins, which then uncontrollably dissolve their own cell envelope. “The combination of these different mechanisms is the reason for the exceptional resilience to resistance,” says Schneider. This shows the potential that still exists in the natural diversity of bacteria that are candidates for new antibiotics.

The research team now plans to use its findings to further increase the effectiveness of clovibactin. “But there is still a long way to go before a new antibiotic hits the market,” says Schneider.

- This press release was originally published on the Universität Bonn website